Method of inhibiting skin irritation

ABSTRACT

A method of inhibiting or reducing the irritation of skin resulting from allergic contact dermatitis, caused by contact with natural or synthetic allergenic agents, e.g. poison ivy, and dinitrochlorobenzene, respectively, is described. The method comprises applying to the skin an irritating reducing effective amount of a protective agent which is an organic compound having at least two polar groups, e.g. carboxyl groups, separated by a chain of at least 15 atoms the majority of which are carbon atoms and optionally containing a cyclic moiety of at least 5 atoms, prior to contact of the skin with the allergenic agent. The protective agent may be combined in a pharmacologically acceptable base for application to the skin.

This is a Division of application Ser. No. 319,030, filed Dec. 27, 1972,now U.S. Pat. No. 4,076,799.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to mitigating or reducing skin irritation inallergic contact dermatitis.

Contact dermatitis manifests itself in an inflamation of the skin. Inmild cases the symptoms are itching, burning or reddening of the skin.In more severe cases vesiculation and edema may be present and may befollowed by weeping and crusting. The most severe cases may beaccompanied by bleeding vesicles and gross edema.

Contact dermatitis can be classified as allergic contact dermatitis oras primary irritant dermatitis. Although the symptoms of both types ofdermatitis are similar there are some basic differences which are widelyrecognized.

Primary irritant dermatitis is the more common form of contactdermatitis and is caused by irritating agents which will causedermatitis in all persons upon sufficient exposure. The period betweencontact with the primary irritant and the onset of symptoms is short orabsent.

Allergic contact dermatitis may be caused by many substances whichcontact the skin. However, in this type of dermatitis a given substancemay cause a dermatological reaction in certain subjects only. Thisreaction usually does not occur with the initial contact, but only uponsubsequent exposures. Moreover, the reaction occurs only in these now"sensitized" subjects and there is a time interval between contact anddevelopment of symptoms. Sensitization is caused by previous contact tothe irritating substance. Some persons never become sensitized, othersrequire numerous contacts and some require only a few contacts forsensitization. Thus, an essential difference is recognized betweenallergic contact dermatitis and primary irritant dermatitis, the latterbeing predictably induced by substances irritating to all persons theformer being erratically induced, if at all, and only aftersensitization.

Among the most common naturally occuring allergens capable ofsensitizing and causing allergic contact dermatitis in a largeproportion of subjects are the antigenic plants of the genus Rhus, suchas poison ivy, poison oak, and poison sumac. The symptoms of reddeningof the skin, formation of an itchy rash and often blistering of the skincommon to all types of contact dermatitis are particularly familiar tomany as a result of contact with poison ivy or other plants of the genusRhus. Such dermatologic reactions are extremely irritating and in severecases can cause temporary incapacitation of an individual. With theadvent of the greater use of the outdoors by people, such as isexperienced in camping, hiking, nature study and similar activities,especially in wooded or relatively less populated areas, the probabilityof contact with skin irritating plants is increased and therefore theneed for protection against irritation resulting therefrom becomesapparent.

While allergic contact dermatitis due to poison ivy, poision oak, poisonsumac and like antigenic plants is widely known it is equally wellestablished that allergic contact dermatitis is caused by a large numberof materials encountered by workers in industry. Such materials may beend products, raw materials, intermediates and by products of industrialprocesses. The problem of occupational allergic contact dermatitis is asignificant one resulting in lost man hours of production, lost wages,discomfort to workers, job changes and workmen's compensation payments.Examples of materials known to cause allergic contact dermatitis amongindustrial and non-industrial workers are dinitrochlorobenzene,insecticides containing pyrethrum or Rotenone, dye intermediates such asaniline, nitro compounds, anthracene and derivatives thereof, benzidineand its compounds, naphthylamines and benzanthrone and its compounds,dyes such as paraphenylenediamine, aniline black, paramido phenol,amido-azo-toluene, amido-azo-benzene, Malachite Green, Metanil Yellow,Nigrosine and Rosaniline, photo developers such as hydroquinone,para-amido-phenol and pyrogallol, rubber accelerators and antioxidantssuch as hexamethylene tetramine, tetramethyl thiuram monosulfide,paratoluidine, phenyl beta naphthylamine and triethyl trimethyltriamine, coal tar and its derivatives such as pyridine andphenanthrene, explosives such as trinitrotoluol, tetranitro-methylaniline, ammonium nitrate and sodium nitrate and synthetic and naturalresins such as wood rosin and phenol formaldehyde.

2. Description of the Prior Art

It is known that protection against skin irritation can be achieved insubjects sensitized to allergens such as plants of the genus Rhus byexposing the subject to a controlled series of contacts with theallergenic irritant. The concentration of allergen, usually in aninnocuous vehicle, in each subsequent controlled exposure can beincreased so as to buildup a degree of immunity to the allergenicsubstance. Such a procedure results in temporary or partial protectionagainst skin irritation caused by contact with the specific allergen orclosely related allergens. However, the procedure, carried out under aphysician's direction is somewhat tedious, inconvenient and oftenuncomfortable. Alternatively, the application of heretofor knownlotions, creams and balms etc. to the skin prior to or even aftercontact with the skin irritant affords an ineffective method ofpreventing or reducing skin irritation due to many materials encounteredby workers in industry and plants of the genus Rhus, such as poison ivy,poison oak and poison sumac.

It is also known that the degree of skin irritation caused by certainprimary irritants, particularly organic detergents, can be prevented orreduced by incorporating agents called "mildness additives" by Kelly andRitter in U.S. Pat. No. 3,630,934, issued Dec. 28, 1972, and in U.S.Pat. No. 3,538,009, issued Nov. 3, 1970. However, the Kelly and Ritterpatents relate to reduction of the irritation from primary irritants andnot to reduction of irritation from agents which cause allergic contactdermatitis following sensitization.

Accordingly, it was surprising to discover that certain compoundsincluding the mildness agents mentioned in the Kelly Ritter patentsmentioned above would also reduce skin irritation due to allergiccontact dermatitis following contact of a sensitized subject withallergens such as found in industry and genus Rhus plants.

OBJECT OF THE INVENTION

It is an object of this invention to reduce the amount of skinirritation due to allergic contact dermatitis caused by contact with anallergen following sensitization to that allergen.

Another more specific object of the present invention is to provent orreduce skin irritation resulting from contact of the skin withirritating plants of the genus Rhus. Another more specific object of thepresent invention is to prevent or reduce skin irritation resulting fromcontact of the skin with allergenic agents formed or used in industrialprocesses.

It is a still further object of this invention to provide a methodwherein lotion and cream compositions containing a protective agent areapplied to the skin to prevent dermatologic reaction of the skin due tocontact with skin irritating allergenic agents.

SUMMARY OF THE INVENTION

Broadly stated, this invention involves the application of skinirritating reducing effective amounts of compositions containingmaterials called "protective agents" to the skin prior to contact withagents capable of causing allergic contact dermatitis, for exampleplants of the genus Rhus, to eliminate or reduce the dermatologicalreaction. The so-called "protective agent" can be generalized as anorganic compound containing at least two polar groups which areseparated by a chain of at least 15 atoms a majority of which are carbonatoms and optionally containing a cyclic moiety of at least 5 atoms. Theprotective agent may be dispersed or dissolved in a pharmaceuticallyacceptable base, such as the type used in hand lotions, hand creams andaerosol sprays, typically used for compositions intended for applicationto the skin.

As used herein, the term "polar group"is meant to define a group havinga dipole moment and containing at least one nitrogen, oxygen,phosphorus, sulfur atom or combinations thereof. These groups are deemedto be capable of hydrogen bonding with the protein, although theformation of stronger bonds, such as covalent bonds, is not excluded.The optional cyclic moiety is preferably carbocyclic, i.e. cyclichydrocarbon moiety of 5 to 18 carbon atoms which can be saturated or cancontain from 1 to 9 double bonds and can contain one or moresubstituents on the ring. Heterocyclic moieties which contain thestructures --O--, --S--, --N--, or --NH-- in the ring can also bepresent in the protective agent and serve as the cyclic moiety.

In accordance with the method of the present invention, it has beendiscovered that the symptoms of allergic contact dermatitis caused bycontact of irritating allergenic agents with the skin can be reduced oreliminated by applying to the skin the protective agent prior to contactwith such irritating allergenic agents. Evidence, such aselectrophoretic studies of mixtures of soluble proteins and protectiveagents, indicates that some form of interaction occurs between thekeratin layer of the skin and the protective agents. Although thecomplex formed between protein molecules and the protective agent can beisolated by the electrophoresis, the specific nature of the complex hasnot yet been established. It is presumed, however, that both adsorptionand some form of chemical interaction are involved. It is furthertheorized that the chain of at least 15 atoms can aid in the adsorptionof the protective agent onto the keratin layer of the skin and that thepolar groups of the protective agent interact with the protein moleculesof the keratin layer.

In addition to the requirement that the protective agent contain atleast two polar groups, the polar groups of the protective agent mustalso be separated by a chain of at least 15 atoms, a majority of whichshould be carbon atoms. However, the presence of additional polar groupslocated intermediary to the described two terminal polar groups does notappear to interfere in the effectiveness of the protective agent. It isbelieved that as a result of this chain length the indicated polargroups are capable of, and do interact with different protein molecules.

The resulting irritation of the skin by an irritating agent is believedto be caused by the permission of an irritating substance into either orboth the pilosebaceous duct and/or the surface of the epidermis. Thepermeation through the pilosebaceous duct and/or the epidermis, causesdamage to occur to the contacted viable cells of either or bothanatomical sections of the skin. Further dermal insults are believed toresult in the allergic syndromes which are manifested by so-calledchallenge dosages. The protective agents, employed in the methods of thepresent invention, are believed to counteract this permeating ability ofthe allergen. The protective agents are believed to provide additionalbridges between the protein molecules of the keratin layer and/orpilosebaceous duct cells, thereby maintaining the integrity of the skinsurface or duct wall. This in turn prevents the permeation of theirritating substance (allergen) to pass through these skin regions. Itis to be understood, however, that we do not wish to be bound by theforegoing explanation of the activity of the protective agents of themethod of the present invention, and that such explanation is only setforth for a better understanding of the present invention.

The protective agents utilized in the present invention are compoundswhich contain at least two polar groups separated by an organic radicalof at least 15 atoms, a majority of which are carbon atoms. The organicradical separating the polar groups optionally contains a cyclic group.Additional polar groups may be present in this organic radical or may belocated on branches attached to this radical. Such additional polargroups do not interfere in the effectiveness of the protective agent.The two polar groups described can be the same or different. Suitablepolar groups include hydroxyl (--OH); carboxyl (--COOH); ester(R'O--CO--, wherein R' can be an aliphatic, cycloaliphatic, or aromaticradical of 1-12 carbon atoms, or can be part of a polyester chain; amino(--NH₂); substituted amino (NHR" or --NR"R"', wherein R" or R"' arealiphatic or aromatic hydrocarbon radicals of 1-12 carbon atoms, orwherein R" and R"' can combine to form 3-to 6-membered rings with thenitrogen, or wherein R" is part of a polyamine chain); amido ##STR1##substituted amido ##STR2## wherein R^(IV) and R^(V) are aliphatic oraromatic hydrocarbon radicals of 1-12 carbon atoms or wherein R^(IV) andR^(V) can combine to form 3 to 6 membered rings with the nitrogen orR^(IV) can be part of a polyamide chain); quaternary ammonium salts##STR3## where R^(VI), R^(VII), and R^(VIII) are lower alkyl radicalsand X⁻ is is an anion such as a halogen ion); sulfate (--SO₄ Me, whereMe is a metal and preferably an alkali metal); sulfonate (--SO₃ Me);sulfonamide (--SO₂ NH₂); substituted sulfonamide (--SO₂ NHR^(IV) or--SO₂ NR^(IV) R^(V)), thio acid salts (--COSMe); thioesters ##STR4##sulfoxides (═SO); sulfonic acid (--SO₃ H); sulfinic acid (--SO₂ H);phosphate (--HMePO₄ or --Me₂ PO₄); and phosphonium salts (--HPO₃ Me).The preferred polar groups employed in the protective agents of themethod of the present invention are those which contain, aside from anymetal or halogen which may be associated with the polar group in ionicform, carbon and oxygen or carbon and nitrogen. In general, functionalgroups of greater polarity are preferred over those of lesser polarity.It will be apparent that the size of any of the described substituentsand particularly hydrocarbon substituents on the polar group will affectthe polarity.

In general, the preferred substituents where aliphatic or aromaticradicals of 1-12 carbon atoms are mentioned, are those of fewest carbonatoms. For example, aliphatic radicals which are preferred are loweralkyl or alkenyl radicals containing 1-4 carbon atoms. As the aromaticradical phenyl is preferred and may be substituted with alkyl radicalsof 1-4 carbon atoms. Aralkyl radicals, especially phenyl-lower alkylradicals containing 1-4 carbon atoms in the lower alkyl group, are notexcluded. Benzyl is the preferred aralkyl radical.

Aliphatic radicals of short or long chains containing water-solubilizinggroups such as polyoxyalkylene groups, especially polyethylene glycolchains, are of considerable interest.

The presence of more than two polar groups each of which are separatedby 15 or more atoms increases the effectiveness of a protective agent inwhich the polar groups are weak polar groups, such as hydroxyl groups,but does not appear to add significantly to the effectiveness of aprotective agent containing at least two strong polar groups such ascarboxyl groups separated by the necessary linking chain.

Although the minimum size of the linking radical is determined by thelength of the chain separating the polar groups, the maximum size of thelinking radical could be determined by the dispersibility or solubilityof the protective agent in the medium in which it is incorporated. Thus,compounds which are not liquid or soluble or colloidally dispersible arenot suitable in preventing allergic reactions. Hence, the upper limit ofthe size of the linking radical is determined not only by the number ofatoms in the linking radical, but also by the presence of additionalpolar groups in the linking radical which can increase the solubility ordispersibility of the protective agent, as well as the nature of anyradical attached to the polar group. In general, however, the linkingradical contains less than 80 atoms. As indicated, the linking radicalhas, preferably, a carbon backbone structure which can be aliphatic,cycloaliphatic, or aromatic in nature. The optional carbocyclic orheterocyclic moiety need not be part of the backbone structure. Thelinking radical can also be in the form of a polymeric structure such asa polyester, polyether, polyamide, or polyamine. Although otherpolymeric linking radicals will be apparent to those skilled in the art,many of these radicals are excluded by virtue of requirements such asliquid state, or solubility or colloidal dispersibility.

The following classes of materials are protective agents suitable foruse in the method of the present invention:

A. The unsaturated polymerized product obtained from the polymerizationof 2 to 4 molecules of a monomeric ethylenically unsaturated C₁₂ to C₂₆fatty acid or the saturated derivative product of said polymerizedproduct, said product or derivative product containing 2 to 4 carboxylgroups; or in place of carboxyl groups derivative radicals selected fromthe group consisting of carboxyl salt; hydroxyl; unsubstituted amino;substituted amino wherein the substituents are aliphatic or aromatichydrocarbon radicals of 1 to 12 carbon atoms, or said substituents takentogether form a 3 to 6 membered carbocyclic or heterocyclic ring withthe amino nitrogen; unsubstituted amido; substituted amido wherein thesubstituents are aliphatic or aromatic hydrocarbon radicals of 1 to 12carbon atoms, or said substituents taken together form a 3 to 6 memberedcarbocyclic or heterocyclic ring with the amido nitrogen; quaternaryammonium wherein the nitrogen substituents are alkyl of 1 to 6 carbonatoms; lower alkyl ester; sulfate; sulfonate; phosphate, phosphonate;and derivative compounds containing further substituents in said alkyl,aliphatic or aromatic hydrocarbon radicals selected from the groupconsisting of carboxyl and the said derivative radicals.

Among the protective agents defined in A which can be utilized in themethod of the invention are fatty polyquaternary ammonium compoundshaving the formula ##STR5## in which R is the hydrocarbon radical of thepolymeric fatty acid, R (COOH)_(n) obtained by polymerization of anunsaturated higher fatty acid containing 12 to 26 carbon atoms;

R₁ is an aliphatic hydrocarbon group having from 1 to 6 carbon atoms;

X is an anion;

Y is an alkylene radical having 1 to 8 carbon atoms;

m is 3 or 4;

n is 2 or 3; and

p is 0, 1 or 2.

The polymeric fatty acids from which the quaternary ammonium compoundsemployed as protective agents in the method of the present invention arederived are polymerization products of unsaturated fatty acidscontaining from 12 to 26 carbon atoms and generally having a degree ofpolymerization of two to four. Quaternary ammonium compounds preparedfrom fatty acid mixtures containing such dimer, trimer, or tetrameracids are also useful. Quaternary ammonium compounds of the type usefulin the method of the present invention are disclosed in U.S. Pat. Nos.3,073,864 and 3,299,138, the disclosure of which patents is incorporatedherein by reference.

B. Condensation products of alkylene oxides having 2 to 4 carbon atomsand polyamines having 2 to 4 amino groups and containing 2 to 8 carbonatoms in an aliphatic, cycloaliphatic or aromatic group. The alkyleneoxide units can be random or block units.

Representative compounds of the above class found to be useful in thisinvention have the formula ##STR6## in which x is from about 2 to 10,and y is from about 2 to 15.

C. Condensation products of ethylene oxide with a hydrophobic baseformed by the condensation of propylene oxide with propylene glycol,having the general formula ##STR7## wherein a is 1 to 150;

b is 15 to 70; and

c is 1 to 150.

D. Esters and polyesters of cycloaliphatic or aromatic polycarboxylicacids containg at least one 5 to 7 carbon ring and a hydroxy compoundselected from the group consisting of

(a) polyoxyalkylene ethers containing 2 to 30 oxyalkylene units whichthe alkylene radical contains 2 to 4 carbon atoms; and

(b) condensation products defined in B and C above.

The benzene, naphthalene, cyclohexane, cyclopentane, cycloheptane anddiphenyl polycarboxylic acids are suitable ring containing acids. Amongthe preferred polycarboxylic acids, are the corresponding dihydrobenzene(cyclohexadiene), tetrahydrobenzene (cyclohexene), polycarboxylic acids.The degree of polymerization can vary widely so long as the requirementthat the compounds contain at least 15 carbon atoms between the polargroups and optionally the proper solubility or dispersibilitycharacteristic in a pharmacologically acceptable base are maintained.The polyoxyalkylene ether can contain further substituents.

E. Esters and polyesters of the polymerized fatty acid product or thesaturated derivative thereof defined in A above and a hydroxy compoundselected from the group consisting of

(a) polyoxyalkylene ethers containing 2 to 30 oxyalkylene units in whichthe alkylene radical contains 2 to 4 carbons atoms; and

(b) condensation products defind in B and C above.

The most preferred protective agents are those of A above. Generally,the polymerized fatty acids contain from 2 to 4 monomeric acid unitsand, consequently, from 2 to 4 carboxyl groups. The polymeric fattyacids can be employed as protective agents, as such, or the carboxylgroups can be altered by known chemical reactions into other polargroups, such as by esterification, amidation, and the like. Thepolymerization of ethylenically unsaturated fatty acids into dimer,trimer, and tetramer acids is known in the art and the products arecommercially available.

The polymerized fatty acids are products obtained by polymerizing 2 to 4molecules of ethylenically unsaturated C₁₂ to C₂₆ fatty acid to giveproducts containing 2 to 4 carboxyl groups comprising the dimer, trimer,tetramer or mixtures thereof, possibly containing some of the startingfatty acid in unpolymerized form. The starting ethylenically unsaturatedacid can be mono- or polyunsaturated. Preferred polymerized fatty acidsare obtained from linoleic acid. The dimer of linoleic acid isespecially preferred. Where polyunsaturated acids are used to preparepolymerized fatty acids. it is believed that the resultant dimer,trimer, or tetramer contains unsaturation. These unsaturated polymerizedfatty acids can be hydrogenated by known procedure to give thecorresponding saturated dimers, trimers, tetramers or mixtures thereof.The saturated derivatives of polymerized fatty acids are also useful inthis invention and are sometimes preferred, especially where color isimportant inasmuch as the saturated derivatives are often of a better,i.e.lighter, color than the corresponding unsaturated material.

Typical of the commerically available polymerized fatty acids useful inthis invention are Empol® Dimer Acids marketed by Emery Industries Inc.Literature supplied by Emery Industries Inc. indicates that reactions atthe carboxyl group of Empol® Dimer Acids are typical of aliphaticcarboxylic acids. Indeed, this has been found to be true. Thus, theconversion of the carboxyl group to any of the other polar groupsmentioned herein is rather simple and analogous to conversions used toprepare the corresponding derivatives of other carboxylic acids.

A number of patents teach methods of preparing polymerized fatty acidswhich are useful in this invention. Among these patents are U.S. Pat.Nos. 2,482,761, 2,793,219 and 3,157,681, the disclosure of which patentsis incorporated herein by reference.

It will be apparent, in view of the foregoing discussion, that theprotective agents need not be pure, but that a mixture of dimer andtrimer acids, and that the protective agent can, furthermore, containcompounds, such as unpolymerized fatty acids, which do not add to theprotective properties of the protective agent. Various polar groups canbe substituted for the carboxyl groups of polymerized fatty acids asdescribed above.

When the protective agent is placed in a pharmacologically acceptablebase, the concentration of the protective agent in such compositions canvary widely, depending on the nature of the base in which it isdissolved or dispersed and other factors. Generally, concentrations ofabout 0.1 to 20% by weight of the weight of the base, more often about0.5 to 10% by weight of the weight of the base, are used.

In one of the methods of this invention, the protective agent isincorporated into a pharmaceutically acceptable base to form a lotion ora cream. While there are a great many formulas for the production ofsuch lotions of creams, most such compositions are emulsions comprisingan emulsifier such as triethanolamine stearate or glycerol monostearate; an emollient such as lanolin, cetyl alcohol, or stearylalcohol; a humectant such as glycerine, sorbitol, mannitol, or theglycols, and various vegetable oils or perfuming agents. Although mostcreams and lotions today are of the emulsion type, the protective agentsto be used in the method of our invention can also be added to the olderhand balms formed of a gum, such as gum tragacanth, in water.

The protective agents used in the method of this invention can beincorporated into lotions or creams which contain other known protectiveagents, such as fatty acids for protection against dry dust, andpetroleum jelly or waxes for protection against aqueous solutions;methyl cellulose and cellulose derivatives for protection againstsolvents, oils and fats.

The protective agents of this invention can also be incorporated intoaerosol sprays and appropriate propellants, emulsifiers, emollients,humectants, perfuming agents and the like, as mentioned above, can beselected.

The following illustration is intended to show how potential protectiveagents are screened without signal use testing on human subjects.

ILLUSTRATION I

This illustration above shows several of the methods which are used todetermine whether a given chemical substance possesses activity as askin protective agent and lists representative materials which have beendetermined to have such activity based on one or more of the describedtests.

Several of the listed protective agents have been tested by each of themethods described below and a number of protective agents have beensubjected to at least two of the tests. Good correlation of results hasbeen found between the various tests. Good correlation has also beenfound between activity in the various tests and actual activity inreducing poison ivy (Examples 1 and 2) and in reducing irritation due toother allergenic agents such as dinitrochlorobenzene (Examples 3-4).

A. ANIMAL IMMERSION TEST

A female, albino guinea pig, weighing about 285 to 345 g, is immersed upto the thoracic region in the test solution at 40° C. for 4.5 hours perday on three successive days. Each animal is thoroughly rinsed and driedafter each immersion. Three days after the last immersions, the skin ofeach animal is examined for gross changes, and grades are assigned whichrepresent the degree of damage to the skin. In general, three animalsare tested simultaneously in the same solution. The grading system isbased on a scale of 1 to 10, in which the numbers have the followingmeanings.

    ______________________________________                                        Grade or                                                                      Rating Gross Reaction        Skin Damage                                      ______________________________________                                        1      Severe cracking and bleeding; death                                                                 Extremely                                               of animal in most instances                                                                         severe; death of                                                              skin tissue                                      2      Severe cracking; moderate bleeding                                                                  Extremely                                                                     severe; death of                                                              skin tissue                                      3      Severe cracking; slight to moderate                                                                 Severe                                                  bleeding                                                               4      Moderate cracking     Severe                                           5      Slight cracking       Moderate                                         6      Severe scaling        Moderate                                         7      Edema, slight to moderate scaling                                                                   Moderate                                         8      Slight scaling and moderate edema                                                                   Slight                                           9      Slight redness and edema                                                                            Slight                                           10     Normal                Normal                                           ______________________________________                                    

Despite the fact that this exposure test is conducted using extremelydilute solutions, it is an exaggerated test, as compared to humanexposure; although it has been established (see Canadian Patent No.639,398) that the test correlates extremely well with the skinirritation effect observed on human skin.

In preparing the test solution, a 100 g concentrate is first preparedwhich is then employed in the test solution in 1% by volumeconcentrations. In order to prepare a homogeneous concentrate which isreadily dilutable, the following additional ingredients were added asindicated: Igepal CA-630, a commercially available nonionic wettingagent of octylphenoxypoly (oxyethylene) ethanol; triethanol amine, andcapric acid. The triethanol amine (TEA) is employed to allow saltformation of mildness additives employed in combination with anionicdetergents and the capric acid is employed for the same purpose incombination with cationic detergents. In general, the primary irritantand the protective agent are each employed in the examples illustratedbelow in a concentration of 15 weight percent based on the described 100g concentrate.

A difference of about 1 units between the control animal (immersed inirritant) and the test animal (immersed in irritant containingprotective agent) under the given conditions is generally considered toindicate a satisfactory protective effect.

A typical primary irritant used in the above-described test is sodiumlauryl sulfate, but a variety of irritant materials have been used,including alkali, such as sodium and ammonium hydroxide. In general, amaterial which exhibits protective properties with a given primaryirritant is found to exhibit similar properties with other primaryirritants. Surprisingly, it has been found that protective agentseffective against primary irritants are also effective against reducingirritation caused by allergens as in plants of the genus Rhus.

Further details of the above-described test are found in Ser. No.696,509 filed Jan. 9, 1968, now U.S. Pat. No. 3,630,934, which isincorporated hereby by reference.

B. OCCLUSIVE PATCH TEST (a modified version of the Finkelstein PatchTest)

Female albino guinea pigs, weighing between 300 and 350 grams areshaved, and one application of 7.4% formalin applied. A quantity of 0.15milliliters of each protective agent is applied to part of the test areaand rubbed into the skin approximately 10 times in each direction. Aftera drying time of 1/2 hour, a solution of the irritant is applied to atest pad which is placed over the test site and secured by tape. The padand tape is then covered by a plastic sheet which is secured at theextremes of the abdominal area. 2.0 cc of trypan blue dye PPS wasinjected into each axilla of the test animal. After 18 hours, the padswere removed and the test sites examined for the degree of intensity ofthe dye which had accumulated at the test site. Dye accmulation wasevaluated on the scale of 0 to 100, 0 being the intensity of dye when noprotective agent was applied, and 100 being no visible dye accumulation.Variations of dye intensity of about 5 % or more between test andcontrol is considered significant. The following scale is also used tointerpret results.

    ______________________________________                                        Rating Scale (% Protectability)                                               ______________________________________                                         80-100        Excellent                                                      70-80          Good                                                           60- 70         Minimal                                                        50-60          Irritating                                                      0-50          Very irritating                                                ______________________________________                                    

C. ELECTROPHORESIS

The prescribed procedure for paper electrophoresis is followed. Thisinvolves placing a sample on a paper strip, mounting the strips in aclosed cell filled with a buffer (pH 8.6 most often used), andconnecting the apparatus to a power supply. Thus, degree of mobility ofthe sample along the strip in a given time can be measured. When appliedto keratin, alone or in combination with protective agents or skinirritatnts or agents which degrade keratin samples, the degree ofmobility indicates that an interaction takes place between protein andthe protective agent, since this combination exhibits a mobility lessthan keratin alone. The combination of keratin and skin irritant orkeratin and an agent which degrades protein, on the other hand, exhibitsa mobility greater than protein alone. The differences in degree ofmobility are indicative of the efficacy of the protective agent.

D. MICROSCOPIC STUDIES

Keratin, particularly hair, is subjected to a degradating agent with andwithout pretreatment with, or incorporation of, a potential protectiveagent. Protective qualities are evidence by reduced physicaldeterioration, especially scaling.

The following materials have been found to possess protective qualitiesfor keratin by one or more of the methods described above. In thefollowing formulae "D" is the divalent carboxyl free residue ofpolymerized fatty acids predominantly comprising dimerized linoleicacid. "T" refers to the trivalent carboxyl free residue of polymerizedfatty acid predominantly comprising trimerized linoleic acid.

    __________________________________________________________________________      [D][CH.sub.2 OH].sub.2                                                        [D][COOCH.sub.3 ].sub.2                                                       [D][CONH.sub.2 ].sub.2                                                        [D][CH.sub.2 NH.sub.2 ].sub.2                                                  ##STR8##                                                                     HO[(CH.sub.2CH.sub.2O).sub.mOC[D]CO.sub.2 ].sub.xH                            m=2 to 30; x=1 to 10                                                          [D][CH.sub.2SO.sub.4 Na].sub.2                                                [D][CH.sub.2SO.sub.3 Na].sub.2                                                HOCH.sub.2[D]COOH                                                           10.                                                                             Dimer acid or soap thereof                                                    [D] [COO.sup.- ].sub.2 [X.sup.+ ].sub.2                                       wherein X is H, Na, K, NH.sub.2 (C.sub.2 H.sub.4 OH).sub.2 or                 NH(CH.sub.2 CH.sub.2 OH).sub.3                                                 ##STR9##                                                                     [D](CH.sub.2NHCH.sub.2CH.sub.2NH.sub.2).sub.2                                 [D](CH.sub.2NHCH.sub.2CH.sub.2CH.sub.3).sub.2                                 [D][CH.sub.2 PO(C.sub.4 H.sub.9).sub.3.sup.⊕  Br.sup.⊖            ].sub.2                                                                        ##STR10##                                                                    [T](COOH).sub.3                                                               [T](CONH.sub.2).sub.3                                                         [T](COONa).sub.3                                                              [T](SO.sub.4 Na).sub.3                                                      20.                                                                             [T](CH.sub. 2 NH.sub.2).sub.3                                                 Reaction product of dimer acid and hydroxy-                                   ethyl ethylene diamine. The product is shown                                  as a diester of dimer acid and consists of a                                  mixture of mono-ester, and half ester-half amide,                             diamide.                                                                      NH.sub.2(CH.sub.2).sub.2NH(CH.sub.2).sub.2 OOC[D]COO(CH.sub.2).sub.2NH(C      H.sub.2).sub.2NH.sub.2                                                        Diester of dimer acid and a polyoxyalkyleneated                               ethylenediamine                                                                ##STR11##                                                                    where x is from about 2 to 10; and y is                                       from about 2 to 15.                                                           Reaction product of dimer acid and N-amino-propyl                             diethanolamine. The product is shown as the                                   diamide, put contains also the ester and ester-                               amide.                                                                         ##STR12##                                                                    Di-ethanolamide of dimer acid.                                                [D][CONHC.sub.2 H.sub.4 OH].sub.2                                             Di-ester of dimer acid and ethylene glycol.                                   [D][COOCH.sub.2 CH.sub.2 OH].sub.2                                            Amide prepared from dimer diamine and acetic acid.                            [D][CH.sub.2 NHCOCH.sub.3 ].sub.2                                             The reaction product of dimer acid and                                        N-cyclohexyl-1, 3-propane diamine.                                             ##STR13##                                                                    Polyethylene glycol ester of dimer acid.                                      [D][COO(C.sub.2 H.sub.4 O).sub. x H].sub.2                                    x = 2 to 30.                                                                  Carbitol diester of dimer acid.                                               [D][COO(C.sub.2 H.sub.4 O).sub.z C.sub.2 H.sub.5 ].sub.2                      z = 2 to 30.                                                                30.                                                                             Propylene glycol diester of dimer acid.                                        ##STR14##                                                                    Dimer sulfate                                                                 [D][CH.sub.2 SO.sub.4 H].sub.2                                                Polymeric ester of N,N-di(2-hydroxyethyl)                                     aniline and dimer acid                                                         ##STR15##                                                                    Octylphenoxypolyethoxyethanol diester of dimer                                acid.                                                                          ##STR16##                                                                    x = 4 to 10.                                                                  Polyester of polypropylene glycol and dimer                                   acid.                                                                         [D][COO(C.sub.3 H.sub.6 O).sub.x OCDCOO(C.sub.3 H.sub.6 O).sub.x              H].sub.2                                                                      x = about 6 to about 25                                                       Polybutylene glycol diester of dimer acid.                                    [D][CO(OC.sub.4 H.sub.8).sub.x OH].sub.2                                      x = 10 to 20                                                                  Dimer glycol diacetate.                                                       [D][CH.sub.2 OOCCH.sub.3 ].sub.2                                              N,N-bis-3-aminopropyl dimer diamine.                                          [D][CH.sub.2 N(C.sub.3 H.sub.6 NH.sub.2).sub.2 ].sub.2                        Oleyloxypolyethoxyethanol diester of dimer acid,                              [D][CO(OC.sub.2 H.sub.4).sub.nO(CH.sub.2).sub.8CHCH(CH.sub.2).sub.7           CH.sub.3 ].sub.2                                                              n = about 10                                                                  Monostearyl-monopolyethylene glycol ester of                                  dimer acid.                                                                   C.sub.17 H.sub.35 OOCDCO[OC.sub.2 H.sub.4 ].sub.x OH                          x = about 9                                                                 40.                                                                             [D][CH.sub.2NHCH.sub.2 CH.sub.2 CH.sub.2 NH.sub.2 ].sub.2                     Mixed ester of reaction of pyromellitic anhydride                             with octylphenoxypolyethoxyethanol and subsequent                             reaction with the polyol resulting from reaction                              of ethylene and propylene oxides with ethylene                                diamine.                                                                       ##STR17##                                                                    x = about 7; y = 9; m = 4 to 10.                                              Tetrakis-(3-carb-octylphenoxypolyethoxybenzoyl)                               ester of the tetrol resulting from ethylene                                   oxide and propylene oxide addition to ethylene                                diamine.                                                                       ##STR18##                                                                    x = about 7; m = 4 to 10; y = about 9.                                        Polyethylene glycol diester of terephthalic acid.                              ##STR19##                                                                    x is 4 to 25.                                                                 Polyethylene glycol diester of tetrahydrophthalic                             acid                                                                           ##STR20##                                                                    x = 4 to 25                                                                   Polypropylene glycol ester of pyromellitic acid                                ##STR21##                                                                    x = 5 to 8                                                                    Tris (octylphenoxypolyethoxyethyl) trimesate                                   ##STR22##                                                                    The tetrol resulting from block addition of                                   propylene oxide and ethylene oxide to ethylene                                diamine.                                                                       ##STR23##                                                                    x is about 7                                                                  y is about 9                                                                   ##STR24##                                                                    a = 1 to 150                                                                  b = 15 to 70                                                                  c = 1 to 150                                                                __________________________________________________________________________

PREFERRED EMBODIMENTS OF THE INVENTION

In a preferred embodiment, one of the protective agents falling withinthe described groups is incorporated into a standard cream base, lotionor aerosol which is applied to the skin prior to contact with the skinirritating plant. The protective agents falling within the disclosedgroups which are currently most preferred are those based on dimerizedfatty acids, specifically dimerized linoleic acid and the correspondingproducts obtained from hydrogenated dimerized linoleic acid. Inparticular, we have found that the dimerized acids which have beenesterified with various alcohols, and particularly with oxyalkylenegroup-containing alcohols, are the most efficacious. However, sincecertain of the protective agents may display different degrees ofsuccess in protecting against various skin irritating allergenic agentsour invention must be construed as encompassing the use of all of thecompounds falling within the above-stated groups. While the examplesbelow set forth the use of compounds which are effective against aspecific skin irritating allergenic agents, it should be understood thatother compounds falling within the groups may be more effective againstother skin irritating allergenic agents.

The following examples illustrate the invention and are not intended tobe limiting in any manner.

EXAMPLE 1

This example illustrates the practice of the invention in reducingirritation of the skin by Rhus oleoresin (i.e. poison ivy extract). Thereduction in irritation was demonstrated on the skin of volunteer malesubjects in the following manner.

The test subjects were first titrated for sensitivity by applying toskin test sites graded concentrations of Rhus oleoresin in HydrophilicOintment U.S.P. A small quantity of the Rhus oleoresin containingointment was applied to the skin by means of a spatula and the sitecovered by a gauze patch for 24 hours, after which the patch was removedand the site observed daily for the next several days. The concentrationof Rhus oleoresin in the Hydrophilic Ointment which was chosen forsubsequent work was that concentration which gave a brisk dermatitis at48 hours. Upon completion of the titration for sensitivity, an ointmentconsisting of 5 to 10% by weight of bis(hydroxyethyl) dimerate inHydrophilic Ointment was applied to a fresh skin test site by rubbing iton. The bis(hydroxyethyl) dimerate was prepared by esterifying acommercial product predominantly comprising dimerized linoleic acid withethylene glycol in an acid:glycol ratio of about 1:2. This treatment wasfollowed by the application, using a spatula, of the Rhus oleoresincontaining ointment to the same site within 2 to 20 minutes after theapplication of the bis(hydroxyethyl) dimerate containing ointment. Thesite was then covered with a gauze patch for 24 hours after which thegauze patch was removed and daily observations made of the test site forthe next 5 days. As a control a separate area of fresh skin was firsttreated by applying thereto the Hydrophilic Ointment alone (i.e. withoutthe dimerate). This treatment was followed at 2 to 20 minutes thereafterby the application of the Rhus oleoresin containing ointment to the samearea, by means of a spatula. A gauze patch was then placed over the areafor 24 hours, after which the patch was removed and daily observationsmade for the next 5 days. The skin area to which the bis(hydroxyethyl)dimerate containing Hydrophilic Ointment had been applied prior to theapplication of the Rhus oleoresin containing ointment exhibited a markedreduction in dermatologic reaction as compared to the control area.

EXAMPLE 2

The procedure of Example 1 was followed except that an ointmentconsisting of 5 to 10% by weight of bis(triethanolamine salt) of dimeracid (dimerized linoleic acid) in Hydrophilic Ointment, instead of thebis(hydroxyethyl) dimerate, was applied to the skin by rubbing, prior tothe application of the Rhus oleoresin containing ointment. Diminishedreaction was observed in the skin area to which the bis(triethanolaminesalt) of dimer acid containing ointment had been applied as compared tothe control skin area.

EXAMPLE 3

This example was carried out using fresh male subjects and employing theprocedure and materials of Example 1, except that dinitrochlorobenzenewas substituted for the Rhus oleoresin. The results obtained werecomparable to the results described in Example 1 with respect to thereduction of irritation.

EXAMPLE 4

The procedure and materials of Example 2 were employed on fresh malesubjects except that dinitrochlorobenzene was substituted for the Rhusoleoresin. The results obtained were comparable to the results describedin Example 2.

We claim:
 1. A method of preventing or reducing irritation of the skinby skin irritating allergenic agents which comprises applying to theskin of a subject sensitized to said allergenic agent prior to contactwith said skin irritating allergenic agent, an irritation reducingeffective amount of a protective agent said agent comprising a compoundcontaining at least two polar groups separated by a chain of at least 15atoms the majority of which are carbon atoms selected from the groupconsising ofthe unsaturated polymerized product obtained from thepolymerization of 2 to 4 molecules of a monomeric ethylenicallyunsaturated C₁₂ to C₂₆ fatty acid or the saturated derivative product ofsaid polymerized product or derivative product containing 2 to 4carboxyl groups; or in place of carboxyl groups derivative radicalsselected from the group consisting of hydroxyl; unsubstituted amino;substituted amino wherein the substituents are aliphatic or aromatichydrocarbon radicals of 1 to 12 carbon atoms, or said substituents takentogether form a 3 to 6 membered carbocyclic or heterocyclic ring withthe amino nitrogen; unsubstituted amido; substituted amido wherein thesubstituents are aliphatic or aromatic hydrocarbon radicals of 1 to 12carbon atoms, or said substituents taken together form a 3 to 6 memberedcarbocyclic or heterocyclic ring with the amido nitrogen; quaternaryammonium wherein the nitrogen substituents are alkyl of 1 to 6 carbonatoms; lower alkyl ester; sulfate; sulfonate; phosphate; phosphonate;and derivative compounds containing further substituents in said alkyl,aliphatic or aromatic hydrocarbon radicals selected from the groupconsisting of carboxyl and the said derivative radicals.
 2. The methodof claim 1 in which said irritation of the skin is an allergic contactdermatitis, said skin irritating allergenic agent is an allergic contactdermatitis producing agent and said protective agent is present in anamount effective to reduce skin irritation produced in the absence ofsaid protective agent.
 3. The method of claim 1 in which said protectiveagent is the ethylene glycol diester of dimerized linoleic acid or thecorresponding saturated derivative.
 4. The method of claim 1 in whichsaid protective agent is the ethylene glycol diester of dimerizedlinoleic acid.
 5. The method of claim 1 in which said protective agentis dissolved or dispersed in a pharmacologically acceptable base in anamount ranging from about 0.1 to about 20 percent by weight of theweight of said base.
 6. The method of claim 1 wherein the protectiveagent is applied to the skin in the form of an aerosol spray.
 7. Themethod of claim 1 wherein said protective agent is applied to the skinin the form of a lotion.
 8. The method of claim 1 wherein saidprotective agent is applied to the skin in the form of a cream.
 9. Themethod of claim 1 wherein said skin irritating allergenic agentscomprise antigenic plants.
 10. The method of claim 9 wherein said plantscomprise plants of the genus Rhus.
 11. The method of claim 10 whereinsaid plants are poison ivy, poison oak and poison sumac.
 12. The methodof claim 1 wherein the said skin irritating allergenic agents are dyesand dye intermediates.
 13. The method of claim 1 wherein the said skinirritating allergenic agents are insecticide compositions and componentsthereof.
 14. The method of claim 1 wherein the said skin irritatingallergenic agents are rubber accelerators and antioxidants.
 15. Themethod of claim 1 wherein the said skin irritating allergenic agents arenatural and synthetic resins.